Alzheimer's disease is a neurodegenerative disease, which is characterized by the degeneration and loss of neuronal cells accompanied by the formation of senile plaques and neurofibrillary tangles. Senile plaque that is the most characteristic in Alzheimer's disease consist of essentially amyloid-.beta. protein (hereinafter referred to as A.beta.) [see Biochem. Biophys. Res. Commun., 122, 1311 (1984)] and other intracerebral components. It is known that A.beta. comprised of 40 or 42 amino acids (hereinafter referred to as A.beta..sub.1-40 and A.beta..sub.1-42, respectively) is toxic to neurons and induces neurofibrillary changes.
Some patients with familial Alzheimer's disease are known to have APP (amyloid precursor protein) gene mutation, and it is well known that the cells transfected with such mutated gene produce and secrete an increased amount of A.beta. [for example, see Nature, 360, 672 (1992); Science, 259, 514 (1993); Science, 264, 1336 (1994), etc.].
Based on the information, medicines which inhibit production and/or secretion are useful for preventing and/or treating diseases caused by A.beta. (e.g., Alzheimer's disease, Down's syndrome, etc).
Alternatively, secreted form of amyloid precursor protein (sAPP) is reported to have neurotrophic factor like property (Neuron, 10, 243-254,1993). As neurotrophic factor like property, 1) survival and preserving effect to the neuronal cell; 2) stimulating the synapse formation; 3) protection of neuronal cell death; and 4) long term potentiation in hippocampus are given as examples. By the above-mentioned property, drugs which stimulate the sAPP secretion are also useful in preventing and treating 1) neurodegenerative diseases such as dementia (e.g., senile dementia, amnesia, etc.), Alzheimer's disease, Down's syndrome, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic sclerosis on lateral fasciculus, Huntington's disease, multiple sclerosis, etc., 2) neurological disorders involved in cerebrovascular disorders (e.g., cerebral infarction, encephalorrhagia, etc.), a head injury or an injury of spinal cord, and so forth.
EP-A-652009 discloses peptide derivatives which is a protease inhibitor exhibiting an A.beta. production inhibiting effect in in vitro experiments using cell lines.
On the other hand, the following bicyclic amine compounds are known.
1) JP-A-2-96552 (U.S. Pat. No. 5,137,901) discloses a compound of the formula: ##STR2## PA0 2) JP-A-63-77842 discloses a compound of the formula: ##STR5## PA0 3) WO 92/15558 discloses a compound of the formula: ##STR6## PA0 4) WO 95/32967 discloses amide derivatives of the formula: ##STR7## PA0 5) EP-A-754455 discloses a pharmaceutical compositions for the therapeutic application as neuroprotectors in Parkinson's and Alzheimer's diseases containing a compound of the formula: ##STR8## PA0 (1) a compound of the formula: ##STR12## PA0 (2) compound (I), wherein PA0 (3) compound (I), wherein Ar is an aromatic ring assembly group which may be substituted; PA0 (4) a compound of the above (3), wherein the aromatic rings of the aromatic ring assembly group are two or three aromatic rings selected from the group consisting of benzene, thiophene, pyridine, pyrimidine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, naphthalene, and benzofuran; PA0 (5) a compound of the above (3), wherein the aromatic ring assembly group is 2-, 3- or 4-biphenylyl; PA0 (6) compound (I), wherein Ar is a 4-biphenylyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C.sub.1-3 alkylenedioxy, nitro, cyano, optionally halogenated C.sub.1-6 alkyl, optionally halogenated C.sub.3-6 cycloalkyl, optionally halogenated C.sub.1-6 alkoxy, optionally halogenated C.sub.1-6 alkylthio, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, 5- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.6-10 aryloxy-carbonyl, C.sub.7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C.sub.1-6 alkylsulfonyl, C.sub.6-10 arylsulfonyl, formylamino, C.sub.1-6 alkyl-carboxamido, C.sub.6-10 aryl-carboxamido, C.sub.1-6 alkoxy-carboxamido, C.sub.1-6 alkylsulfonylamino, C.sub.1-6 alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, C.sub.1-6 alkoxy-carbonyloxy, mono-C.sub.1-6 alkyl-carbamoyloxy, di-C.sub.1-6 alkyl-carbamoyloxy, C.sub.6-10 aryl-carbamoyloxy, nicotinoyloxy and C.sub.6-10 aryloxy; PA0 (7) compound (I), wherein X is a divalent C.sub.1-6 aliphatic hydrocarbon group which may contain an oxygen atom; PA0 (8) compound (I), wherein X is a C.sub.1-6 alkylene; PA0 (9) compound (I), wherein X is a group of the formula: --(CH.sub.2)p-X.sup.1 -- wherein each symbol is as defined above; PA0 (10) a compound of the above (9), wherein p is 1; PA0 (11) a compound of the above (10), wherein X.sup.1 is O; PA0 (12) a compound of the above (10), wherein X.sup.1 is NR.sup.8b wherein R.sup.8b is hydrogen or C.sub.1-6 alkyl-carbonyl; PA0 (13) compound (I), wherein X.sup.1 is a group of the formula: --SO.sub.2 --NR.sup.8 -- wherein each symbol is as defined above; PA0 (14) a compound of the above (13), wherein R.sup.8 is hydrogen; PA0 (15) compound (I), wherein Y is a divalent C.sub.1-6 aliphatic hydrocarbon group; PA0 (16) compound (I), wherein Y is C.sub.1-6 alkylene; PA0 (17) compound (I), wherein R.sup.1 and R.sup.2 each is C.sub.1-6 alkyl; PA0 (18) compound (I), wherein Ring A is a benzene ring substituted by the group of the formula: --X--Ar wherein each symbol is as defined above; PA0 (19) compound (I), wherein Ring B is a 4- to 8-membered ring of the formula: ##STR14## PA0 (20) a compound of the above (19), wherein R.sup.8a is hydrogen, optionally halogenated C.sub.1-6 alkyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.6-10 aryloxy-carbonyl, C.sub.7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocycle carbonyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, 5- or 6-membered heterocycle carbamoyl, C.sub.1-6 alkylsulfonyl or C.sub.6-10 arylsulfonyl; PA0 (21) compound (I), wherein Ring B is a 6-membered carbocyclic or heterocyclic ring substituted by a group of the formula: --Y--NR.sup.1 R.sup.2 wherein each symbol is as defined above; PA0 (22) compound (I), wherein Ring B is a ring of the formula: ##STR15## PA0 (23) a compound of the above (22), wherein Za is ethylene; PA0 (24) compound (I), wherein the fused ring to be formed by Ring A and Ring B is a ring of the formula: ##STR16## PA0 (25) compound (I), wherein Ar is 2-, 3- or 4-biphenylyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C.sub.1-3 alkylenedioxy, nitro, cyano, optionally halogenated C.sub.1-6 alkyl, optionally halogenated C.sub.1-6 alkoxy, optionally halogenated C.sub.1-6 alkylthio, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, formyl and C.sub.1-6 alkyl-carboxamido; PA0 (26) compound (I), which is a compound of the formula: ##STR17## PA0 (27) compound (I), which is a compound of the formula: ##STR18## PA0 (28) compound (I) which is PA0 (29) a process for producing of compound (I), which comprises; PA0 (30) an optical isomer of the compound of the formula: ##STR22## PA0 (31) a pharmaceutical composition which comprises compound (I); PA0 (32) a pharmaceutical composition of the above (31) which is an inhibitor for production and/or secretion of amyloid-.beta. protein; PA0 (33) a pharmaceutical composition of the above (31) which is for preventing and/or treating neurodegenerative diseases caused by amyloid-.beta. protein; PA0 (34) a pharmaceutical composition of the above (32), wherein the neurodegenerative disease caused by amyloid-.beta. protein is Alzheimer's disease; PA0 (35) a method of inhibiting production and/or secretion of amyloid-.beta. protein in mammal, which comprises administering to said mammal an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, carrier or diluent; PA0 (36) a use of compound (I) for manufacturing a pharmaceutical composition for inhibiting production and/or secretion of amyloid-.beta. protein; PA0 (37) an inhibitor for production and/or secretion of amyloid-.beta. protein, which comprises compound (I'); PA0 (38) a method of inhibiting production and/or secretion of amyloid-.beta. protein in mammal, which comprises administering to said mammal an effective amount of compound (I') or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, carrier or diluent; PA0 (39) a use of compound (I') for manufacturing a pharmaceutical composition for inhibiting production and/or secretion of amyloid-.beta. protein, and so forth. PA0 (1) strong bases such as alkali metal or alkaline earth metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (e.g., lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), alkali metal or alkaline earth metal lower-alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc.; PA0 (2) inorganic bases such as alkali metal or alkaline earth metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogencarbonates (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), etc.; or PA0 (3) organic bases such as amines e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]-7-undecene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), etc., basic heterocyclic compounds, e.g., pyridine, imidazole, 2,6-lutidine, etc. PA0 (1) methods for producing 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-acetic acid are disclosed in Synthetic Communications 11, 803-809 (1981), etc.; and PA0 (2) methods for producing 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-carboxylic acid and 1,2,3,4-tetrahydro-6-methoxynaphthalene-2-butyric acid are disclosed in J. Chem. Soc. Perkin Trans. I, 1889-1893 (1976), etc.
wherein Y represents a straight-chain or branched, substituted or unsubstituted alkylene chain having up to 6 carbon atoms; Z represents a group of the formula: --NR.sup.2 R.sup.3, --OR.sup.4, or the like; R.sup.2 and R.sup.3 are identical or different and represent hydrogen, alkyl, alkenyl or cycloalkyl, or represent aryl which may be substituted by halogen, etc.; R.sup.4 represents hydrogen, alkyl, alkenyl, or the like; R.sup.1 represents hydrogen, alkyl, aralkyl, heteroarylalkyl or a group of the formula: --(Y.sup.1 -Z.sup.1) in which Y.sup.1 and Z.sup.1 are identical or different and have the same meanings as Y and Z; A and D each represents a group of the formula: --CH.sub.2, O, S or NR.sup.13. or the moiety of -CH or N of a double bond C.dbd.C or C.dbd.NH, with the proviso that either only A or only D represents oxygen, sulfur or N--R.sup.13 ; R.sup.13 represents hydrogen, alkyl, alkoxy, acyl, alkoxycarbonyl or alkylsulfonyl; B represents a group of the formula: --CH.sub.2 or ##STR3##
or the moiety of --CH or N of a double bond C.dbd.C or C.dbd.N; C represents a group of the formula: ##STR4##
or the moiety of C of a double bond C.dbd.C or C.dbd.N; E and F are identical or different and each represents hydrogen, alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy or a group of the formula: --CONR.sup.2 R.sup.3 in which R.sup.2 and R.sup.3 have the same meanings as above, or E and F together form a substituted or unsubstituted carbocycle having 6 carbon atoms, which is agonist, partial agonist and antagonist on the serotonin receptors and is suitable for the treatment of central nervous system disorders, etc.
wherein n represents 1 or 2; A represents a carbonyl while R.sub.7 is hydrogen, or A represents a group of the formula: --CHR.sub.8 -- wherein R.sub.8 represents hydrogen, alkanoyloxy or alkoxycarbonyl, while R.sub.7 is hydrogen or R.sub.7 and R.sub.8 together form another bond; E represents a straight-chain alkylene which has 3 or 4 carbon atoms and may be substituted by an alkyl; G represents a straight-chain alkylene which has 2 to 5 carbon atoms and may be substituted by an alkyl; R.sub.1 represents hydrogen, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy; R.sub.2 represents hydrogen, halogen atoms, hydroxy, alkoxy, phenylalkoxy or alkyl; or R.sub.1 and R.sub.2 together form an alkylenedioxy having 1 or 2 carbon atoms; R.sub.3 represents hydrogen, alkenyl or alkyl having 3 to 5 carbon atoms; R.sub.4 represents hydrogen, halogen atoms, alkyl, or the like; R.sub.5 represents hydrogen, halogen atoms, alkyl, or the like; and R.sub.6 represents hydrogen, halogen atoms, alkyl, or the like, which is suitable for the treatment of sinus tachycardia and also for the prevention and treatment of ischemic heart disease because of its pharmacological action, decrease in the heart rate and oxygen demand of the heart.
wherein n represents an integer of 1 to 4, which is an intermediate of a compound having a thromboxane A.sub.2 antagonistic effect.
wherein A is CONR where R is hydrogen or C.sub.1-6 alkyl; Q is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R.sub.1 is hydrogen, halogen, etc.; R.sub.2 and R.sub.3 are independently hydrogen, halogen, etc.; R.sub.4 and R.sub.5 are independently hydrogen or C.sub.1-6 alkyl; R.sub.6 is halogen, hydroxy, etc.; R.sub.7 and R.sub.8 are independently hydrogen, C.sub.1-6 alkyl, aralkyl, or together with the nitrogen atom to which they are attached from an optionally substituted 5 to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur; m is 0 to 4; and n is 0, 1 or 2, which has 5HT.sub.1D receptor antagonist activity and is useful for the treatment of various CNS disorders.
wherein X is H. halogen, alkoxy, alkyl, alkylthio, aryl, aryloxy; R is H, CH.sub.3 or other aliphatic, alicyclic or aryl radicals; R' is H, CH.sub.3 or other aliphatic or alicyclic C.sub.1 -C.sub.3 radicals, or an aryl or arylalkyl, or a radical the same as those indicated for R"; and R" is H, CH.sub.3 or other aliphatic or alicyclic C.sub.1 -C.sub.3 radicals, or an aryl or arylalkyl, or an acetylene or allene group, being potent selective monoamine oxydase B inhibitors.
The conventional A.beta. production inhibitors for the treatment of Alzheimer's disease are problematic in their oral absorbability, stability, etc. and are therefore unsatisfactory as medicines. It is desired to develop a compound which is different from the known compounds mentioned above in its chemical structure and which have an excellent inhibitory effect on A.beta. production and/or secretion and is therefore satisfactorily used in medicines.